1. Field of the Invention
This invention relates to compositions of poorly soluble or water soluble drugs which provide poor bioavailability or are irregularly absorbed following oral administration of their solid dosage forms. More specifically, the herein disclosed invention relates to new compositions of matter containing poorly soluble or water insoluble drugs, a nontoxic water soluble polymer and a wetting agent. The invention further relates to a process for preparing and a method for using the disclosed compositions which compositions provide a high order of drug bioavailability. In the main, the invention will be illustrated with the known antifungal griseofulvin.
2. Description of the Prior Art
Many drugs give an incomplete and irregular absorption when taken orally, particularly poorly water soluble or water insoluble compounds such as griseofulvin and many steroids. One of the earlier attempts to enhance the availability or bioavailability of such drugs relied on mechanical micronization of the pure compounds in order to decrease their particle size. While micronization did enhance absorption over the use of unmicronized material, absorption of the drug was still incomplete. Further the degree of micronization which can be achieved is limited and the micronized particles tend to agglomerate, thus diminishing both the solubility of the drug and its bioavailability. U.S. Pat. No. 2,900,304 is an illustration of griseofulvin compositions for oral or parenteral administration employing micronized drug particles.
Another approach for attempting to enhance the bioavailability of griseofulvin was studied by Marvel et al and reported in The J'l of Investigative Dermatology, 42, 197-203 (1964). Their studies related to the effect of a surfactant and particle size on the bioavailability of griseofulvin when orally administered. Results of their studies indicated that bioavailability of the drug was enhanced when administered in very dilute solutions or aqueous suspensions. Their results further tended to confirm that enhanced bioavailability was obtained with griseofulvin having a higher specific surface area, at least when administered in full daily divided doses. With respect to the effect of the surfactant sodium lauryl sulfate incorporated into grisefulvin tablets, their results demonstrated some initial enhancement of bioavailability with regularly particle sized drug and very little enhancement with micronized drug in comparison to surfactant-free tablets. These investigators further reported that when the daily dose was divided, the surfactant had no enhancing effect.
Still another approach for the enhancement of drug bioavailability is represented by the work of Tachibana and Nakamura in Kollid-Zeitschrift and Zeitschrift Fur Polymere, 203, pgs. 130-133 (1965) and Mayershohn et al in the Journal of Pharmaceutical Science, 55, pgs. 1323-4 (1966). Both publications deal with the use of polyvinylpyrrolidone (PVP) for forming dispersions of a drug. Tachibana discusses the role of PVP in forming very dilute colloidal dispersions of .beta.-carotene in PVP. Mayersohn further prepared solid dispersions or solid solutions of griseofulvin in PVP and the reported results show dissolution rates for the drug increasing with increasing proportions of PVP. This last publication further reported that in the absence of wetting agent in the dissolution medium, the enhancement of the dissolution rate is still greater.
Canadian Pat. No. 987,588 of Riegelman et al, similarly discloses the use and process for making solid dispersions of a drug for enhancing its dissolution rate and bioabailability. In this case the solvents employed were polyethylene glycol (PEG) having molecular weights ranging from 4,000 to 20,000, pentaerythritol, pentaerythritol tetraacetate and monohydrous citric acid. Riegelman postulated that these solvents provided a matrice for griseofulvin which retards crystallization during the solidification process resulting in an ultramicrocrystalline form of the drug with correspondingly faster dissolution. Riegelman's results tend to support this finding of faster dissolution rates for solid solutions of griseofulvin over those of unmicronized, non-wetted micronized and wetted micronized griseofulvin. But his findings were limited to those solid solutions which contain less than 50 percent by weight of the drug since the results demonstrated a slowing of the dissolution rate with higher concentrations of griseofulvin. Riegelman further concluded that the rate of dissolution for a composition having the same ratio of drug to solvent varies significantly depending on the method of preparation, with melt mixing at elevated temperatures in a volatile solvent providing the preferred mode or process.
Another process for preparing ultramicrocrystalline drug particles to increase dissolution of a drug is disclosed by Melliger in Belgian Pat. No. 772,594. That process is characterized by preparing a solution of the drug, PVP and urethane and subsequently removing the urethane. It was reported that, in general, satisfactory results were obtained using solutions in which the quantity of drug represented up to 50 percent by weight of the quantity of PVP present.
U.S. Pat. Nos. 3,673,163 and 4,024,240 respectively are further illustrations relating to the use of PVP in solid dispersions. In the first-cited patent, coprecipitates of acronycine with polyvinylpyrrolidone were prepared in proportions weighted to the polymer to increase the solubility of the coprecipitated acronycine. In the second-cited patent solid antibiotic dispersions containing the antibiotic designated A-32390, in proportions again weighted toward the PVP co-dispersant, were disclosed. Further examples of antibiotic combinations containing PVP are disclosed in U.S. Pat. No. 3,577,514 wherein the PVP is used as a binding agent; and in U.S. Pat. Nos. 3,485,914 and 3,499,959, wherein the PVP is used to sustain the release of the antibiotic. PVP has also been used as a stabilizer with nitroglycerin to retard migration between nitroglycerin tablets as disclosed in U.S. Pat. No. 4,091,091.
With respect to processes employed in preparing certain PVP-griseofulvin compositions, Junginger in Pharm. Ind. 39, Nr. 4 at pgs. 384-388 and Nr. 5 at pgs. 498-501 (1977), reported that spray-dried products provided systems with higher energy levels in comparison with those of simple mixtures and coprecipitates, and correspondingly greater dissolution rates. Junginger further disclosed that the dissolution rates of the simple mixtures were higher when the PVP contents were increased.
In a further attempt to increase the bioavailability of griseofulvin, the drug was treated with small amounts of hydroxypropyl cellulose and formulated into capsules, see Fell et al, J. Pharm. Pharmac., 30, 479-482 (1978). While the formulation produced by this treatment increases the rate and extent of availability of micronized griseofulvin, and authors reported that the treated formulation does not always lead to complete absorption from the upper intenstine as was reported for the Riegelman solid disperse system with polyethylene glycol 6000.